Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury

Dorsal root injury is known to induce alteration of the extracellular environment in the spinal cord and synaptic reorganization with degradation of injured primary afferent and sprouting of spared terminal. These changes affect behavioral sensitivity and sometimes lead to neuropathic pain. We have hypothesized that changes in extracellular proteolysis in the dorsal horn is involved in neuroplastic changes in the dorsal horn after nerve injury. Tissue type plasminogen activator (tPA) is a well-known extracellular serine protease and is involved in the modification of the extracellular matrix, which leads to neuroplastic changes such as long-term potentiation in the hippocampus. In the present study, we found a marked induction of tPA in activated astrocytes following L4/5 root injury and a resultant increase of proteolytic enzymatic activity in the dorsal horn. We also examined the involvement of tPA activity on mechanical hypersensitivity using a root ligation model which has been used for investigating radiculopathy pain behavior. Intrathecal and continuous administration of tPA inhibitor, tPA-STOP, suppressed root ligation-induced mechanical allodynia in a dose-dependent manner during an early stage of injury (0-4 days). In contrast, the delayed administration of tPA-STOP during the chronic stage of injury (10 days) did not affect pain behavior. These data suggest an important contribution of astrocytes in the dorsal horn to the pathophysiology of radiculopathy pain, and astrocyte-derived tPA and the proteolytic activity in the dorsal horn may be one of the essential factors involved in pain following root injury. (c) 2007 Wiley-Liss, Inc.